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Kafle A, Suttiprapa S, Muhammad M, Tenorio JCB, Mahato RK, Sahimin N, Loong SK. Epigenetic Biomarkers and the Wnt/β-Catenin Pathway in Opisthorchis viverrini-associated Cholangiocarcinoma: A Scoping Review on Therapeutic Opportunities. PLoS Negl Trop Dis 2024; 18:e0012477. [PMID: 39236081 PMCID: PMC11407677 DOI: 10.1371/journal.pntd.0012477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 09/17/2024] [Accepted: 08/19/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND Epigenetic modifications, such as DNA methylation and histone modifications, are pivotal in regulating gene expression pathways related to inflammation and cancer. While there is substantial research on epigenetic markers in cholangiocarcinoma (CCA), Opisthorchis viverrini-induced cholangiocarcinoma (Ov-CCA) is overlooked as a neglected tropical disease (NTD) with limited representation in the literature. Considering the distinct etiological agent, pathogenic mechanisms, and pathological manifestations, epigenetic research plays a pivotal role in uncovering markers and potential targets related to the cancer-promoting and morbidity-inducing liver fluke parasite prevalent in the Great Mekong Subregion (GMS). Emerging studies highlight a predominant hypermethylation phenotype in Opisthorchis viverrini (O. viverrini) tumor tissues, underscoring the significance of abnormal DNA methylation and histone modifications in genes and their promoters as reliable targets for Ov-CCA. PRINCIPAL FINDINGS Relevant published literature was identified by searching major electronic databases using targeted search queries. This process retrieved a total of 81 peer-reviewed research articles deemed eligible for inclusion, as they partially or fully met the pre-defined selection criteria. These eligible articles underwent a qualitative synthesis and were included in the scoping review. Within these, 11 studies specifically explored Ov-CCA tissues to investigate potential epigenetic biomarkers and therapeutic targets. This subset of 11 articles provided a foundation for exploring the applications of epigenetics-based therapies and biomarkers for Ov-CCA. These articles delved into various epigenetic modifications, including DNA methylation and histone modifications, and examined genes with aberrant epigenetic changes linked to deregulated signalling pathways in Ov-CCA progression. CONCLUSIONS This review identified epigenetic changes and Wnt/β-catenin pathway deregulation as key drivers in Ov-CCA pathogenesis. Promoter hypermethylation of specific genes suggests potential diagnostic biomarkers and dysregulation of Wnt/β-catenin-modulating genes contributes to pathway activation in Ov-CCA progression. Reversible epigenetic changes offer opportunities for dynamic disease monitoring and targeted interventions. Therefore, this study underscores the importance of these epigenetic modifications in Ov-CCA development, suggesting novel therapeutic targets within disrupted signalling networks. However, additional validation is crucial for translating these novel insights into clinically applicable strategies, enhancing personalised Ov-CCA management approaches.
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Affiliation(s)
- Alok Kafle
- Department of Tropical Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- WHO Collaborating Centre for Research and Control of Opisthorchiasis, Khon Kaen University, Khon Kaen, Thailand
| | - Sutas Suttiprapa
- Department of Tropical Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- WHO Collaborating Centre for Research and Control of Opisthorchiasis, Khon Kaen University, Khon Kaen, Thailand
| | - Mubarak Muhammad
- Department of Physiology and Graduate School, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Jan Clyden B. Tenorio
- Department of Tropical Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- WHO Collaborating Centre for Research and Control of Opisthorchiasis, Khon Kaen University, Khon Kaen, Thailand
| | | | - Norhidayu Sahimin
- Tropical Infectious Diseases Research & Education Centre, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Shih Keng Loong
- Tropical Infectious Diseases Research & Education Centre, Universiti Malaya, Kuala Lumpur, Malaysia
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Catanzaro E, Gringeri E, Burra P, Gambato M. Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies. Cancers (Basel) 2023; 15:4947. [PMID: 37894314 PMCID: PMC10604939 DOI: 10.3390/cancers15204947] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), accounting for 2-8% of cases and being the leading cause of death in these patients. The majority of PSC-associated CCAs (PSC-CCA) develop within the first few years after PSC diagnosis. Older age and male sex, as well as concomitant inflammatory bowel disease (IBD) or high-grade biliary stenosis, are some of the most relevant risk factors. A complex combination of molecular mechanisms involving inflammatory pathways, direct cytopathic damage, and epigenetic and genetic alterations are involved in cholangiocytes carcinogenesis. The insidious clinical presentation makes early detection difficult, and the integration of biochemical, radiological, and histological features does not always lead to a definitive diagnosis of PSC-CCA. Surveillance is mandatory, but current guideline strategies failed to improve early detection and consequently a higher patient survival rate. MicroRNAs (miRNAs), gene methylation, proteomic and metabolomic profile, and extracellular vesicle components are some of the novel biomarkers recently applied in PSC-CCA detection with promising results. The integration of these new molecular approaches in PSC diagnosis and monitoring could contribute to new diagnostic and surveillance strategies.
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Affiliation(s)
- Elisa Catanzaro
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Center, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Patrizia Burra
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Martina Gambato
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
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Zhong B, Liao Q, Wang X, Wang X, Zhang J. The roles of epigenetic regulation in cholangiocarcinogenesis. Biomed Pharmacother 2023; 166:115290. [PMID: 37557012 DOI: 10.1016/j.biopha.2023.115290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023] Open
Abstract
Cholangiocarcinoma (CCA), a heterogeneous malignancy of bile duct epithelial cells, is characterized by aggressiveness, difficult diagnosis, and poor prognosis due to limited understanding and lack of effective therapeutic strategies. Genetic and epigenetic alterations accumulated in CCA cells can cause the aberrant regulation of oncogenes and tumor suppressors. Epigenetic alterations with histone modification, DNA methylation, and noncoding RNA modulation are associated with the carcinogenesis of CCA. Mutation or silencing of genes by various mechanisms can be a frequent event during CCA development. Alterations in histone acetylation/deacetylation at the posttranslational level, DNA methylation at promoters, and noncoding RNA regulation contribute to the heterogeneity of CCA and drive tumor development. In this review article, we mainly focus on the roles of epigenetic regulation in cholangiocarcinogenesis. Alterations in epigenetic modification can be potential targets for the therapeutic management of CCA, and epigenetic targets may become diagnostic biomarkers of CCA.
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Affiliation(s)
- Baiyin Zhong
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Qicheng Liao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Xin Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Xiaonong Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Jianhong Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China; Ganzhou Key Laboratory of Hepatocellular Carcinoma, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China.
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HOXD8 hypermethylation as a fully sensitive and specific biomarker for biliary tract cancer detectable in tissue and bile samples. Br J Cancer 2022; 126:1783-1794. [PMID: 35177798 PMCID: PMC9174245 DOI: 10.1038/s41416-022-01738-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/21/2022] [Accepted: 02/02/2022] [Indexed: 12/13/2022] Open
Abstract
Background Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations. Methods Study design included statistical power and sample size estimation. A genome-wide methylation study of an explorative cohort (50 BTC and ten matched non-tumoral tissue samples) has been performed. BTC-specific altered CpG islands were validated in over 180 samples (174 BTCs and 13 non-tumoral controls). The final biomarkers, selected by a machine-learning approach, were validated in independent tissue (18 BTCs, 14 matched non-tumoral samples) and bile (24 BTCs, five non-tumoral samples) replication series, using droplet digital PCR. Results We identified and successfully validated BTC-specific DNA methylation alterations in over 200 BTC samples. The two-biomarker panel, selected by an in-house algorithm, showed an AUC > 0.97. The best-performing biomarker (chr2:176993479-176995557), associated with HOXD8, a pivotal gene in cancer-related pathways, achieved 100% sensitivity and specificity in a new series of tissue and bile samples. Conclusions We identified a novel fully efficient BTC biomarker, associated with HOXD8 gene, detectable both in tissue and bile by a standardised assay ready-to-use in clinical trials also including samples from non-invasive matrices.
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Rimini M, Puzzoni M, Pedica F, Silvestris N, Fornaro L, Aprile G, Loi E, Brunetti O, Vivaldi C, Simionato F, Zavattari P, Scartozzi M, Burgio V, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021; 15:1367-1383. [PMID: 34669536 DOI: 10.1080/17474124.2021.1991313] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Puzzoni
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Silvestris
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Lorenzo Fornaro
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy
| | - Caterina Vivaldi
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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Khamko R, Daduang J, Settasatian C, Limpaiboon T. OPCML Exerts Antitumor Effects in Cholangiocarcinoma via AXL/STAT3 Inactivation and Rho GTPase Down-regulation. Cancer Genomics Proteomics 2021; 18:771-780. [PMID: 34697068 DOI: 10.21873/cgp.20296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/09/2021] [Accepted: 10/12/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/AIM Opioid-binding protein/cell adhesion molecule-like (OPCML) plays a crucial role in the suppression of tumor progression in several cancer types. Nevertheless, the association between OPCML functions and cholangiocarcinoma (CCA) progression remains unknown. We aimed to investigate biological functions of OPCML and related signaling pathways in CCA cell lines. MATERIALS AND METHODS Methylation status and ectopic expression of OPCML were determined in CCA cell lines using methylation-specific polymerase chain reaction and pcDNA3.1+/C-(K)DYK-OPCML, respectively. Cell proliferation, migration and invasion were investigated. RESULTS OPCML was found to be epigenetically silenced by DNA methylation. Ectopic expression of OPCML inhibited CCA proliferation by inducing apoptosis via AXL receptor tyrosine kinase/signal transducer and activator of transcription 3 (AXL/STAT3) inactivation. It also suppressed cell migration and invasion via down-regulation of Rho GTPases, ras homolog family member A (RHOA), Rac family small GTPase 1 (RAC1) and cell division cycle 42 (CDC42). CONCLUSION We are the first to unravel the antitumor effects and the related signaling pathways of OPCML in CCA. The loss of OPCML expression due to promoter hypermethylation can cause a decrease in cell death but increase in cell migration and invasion, which may at least in part contribute to CCA progression.
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Affiliation(s)
- Ricuphan Khamko
- Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand.,Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Jureerut Daduang
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Chatri Settasatian
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Temduang Limpaiboon
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand; .,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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Majchrzak-Celińska A, Zielińska-Przyjemska M, Wierzchowski M, Kleszcz R, Studzińska-Sroka E, Kaczmarek M, Paluszczak J, Cielecka-Piontek J, Krajka-Kuźniak V. Methoxy-stilbenes downregulate the transcription of Wnt/β-catenin-dependent genes and lead to cell cycle arrest and apoptosis in human T98G glioblastoma cells. Adv Med Sci 2021; 66:6-20. [PMID: 33238230 DOI: 10.1016/j.advms.2020.11.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 09/14/2020] [Accepted: 11/06/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE Glioblastoma is the most common and the deadliest brain cancer. The aim of this study was to analyze the impact of resveratrol and its five analogs: 3,4,4'-trimethoxy, 3,4,2'-trimethoxy, 3,4,2',4'-tetramethoxy, 3,4,2',6'-tetramethoxy and 3,4,2',4',6'-pentamethoxy-trans-stilbenes (MS) on human glioblastoma T98G cells. MATERIALS AND METHODS The Parallel Artificial Membrane Permeation Assay (PAMPA) was used for the prediction of blood-brain barrier penetration ability of the tested stilbenes (PAMPA-BBB). MTT test was applied to analyze the cytotoxicity of the compounds, whereas their ability to inhibit Wnt/β-catenin target genes expression was verified using qPCR. The potential DNA demethylating properties of the analyzed compounds were tested by Methylation-Sensitive High Resolution Melting (MS-HRM). Cell cycle distribution was tested using Fluorescence-Activated Cell Sorting (FACS), whereas apoptosis was analyzed using FITC Annexin V/propidium iodide double staining assay and Western blot. RESULTS High blood-brain barrier permeability coefficient was obtained for both resveratrol as well as methoxy-stilbenes. Their ability to downregulate the expression of Wnt/β-catenin pathway-related genes was confirmed. The 4'-methoxy substituted derivatives showed higher activity, whereas 3,4,4'-tri-MS was the most potent Wnt/β-catenin pathway inhibitor. None of the compounds affected DNA methylation level of MGMT, SFRP1, or RUNX3, despite inducing moderate changes in the level of expression of epigenetic modifiers DNMT3B and TET1-3. Importantly, treatment with 3,4,4'-tri-MS and 3,4,2',4'-tetra-MS led to cycle arrest in the S phase and induced apoptosis. CONCLUSIONS Both, resveratrol, as well as its synthetic methoxy-derivatives, should be further studied as promising adjuvants in glioblastoma treatment.
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Majchrzak‐Celińska A, Dybska E, Barciszewska A. DNA methylation analysis with methylation-sensitive high-resolution melting (MS-HRM) reveals gene panel for glioma characteristics. CNS Neurosci Ther 2020; 26:1303-1314. [PMID: 32783304 PMCID: PMC7702229 DOI: 10.1111/cns.13443] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/07/2020] [Accepted: 07/11/2020] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Local DNA hypermethylation is a potential source of cancer biomarkers. While the evaluation of single gene methylation has limited value, their selected panel may provide better information. AIMS This study aimed to analyze the promoter methylation level in a 7-gene panel in brain tumors and verifies the usefulness of methylation-sensitive high-resolution melting (MS-HRM) for this purpose. METHODS Forty-six glioma samples and one non-neoplastic brain sample were analyzed by MS-HRM in terms of SFRP1, SFRP2, RUNX3, CBLN4, INA, MGMT, and RASSF1A promoter methylation. The results were correlated with patients' clinicopathological features. RESULTS DNA methylation level of all analyzed genes was significantly higher in brain tumor samples as compared to non-neoplastic brain and commercial, unmethylated DNA control. RASSF1A was the most frequently methylated gene, with statistically significant differences depending on the tumor WHO grade. Higher MGMT methylation levels were observed in females, whereas the levels of SFRP1 and INA promoter methylation significantly increased with patients' age. A positive correlation of promoter methylation levels was observed between pairs of genes, for example, CBLN4 and INA or MGMT and RASSF1A. CONCLUSIONS Our 7-gene panel of promoter methylation can be helpful in brain tumor diagnosis or characterization, and MS-HRM is a suitable method for its analysis.
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Affiliation(s)
| | - Emilia Dybska
- Department of Pediatric Gastroenterology and Metabolic DiseasesPoznan University of Medical SciencesPoznańPoland
| | - Anna‐Maria Barciszewska
- Intraoperative Imaging UnitChair and Department of Neurosurgery and NeurotraumatologyPoznan University of Medical SciencesPoznańPoland
- Department of Neurosurgery and NeurotraumatologyHeliodor Swiecicki Clinical HospitalPoznańPoland
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Lian B, Li H, Liu Y, Chai D, Gao Y, Zhang Y, Zhou J, Li J. Expression and promoter methylation status of OPCML and its functions in the inhibition of cell proliferation, migration, and invasion in breast cancer. Breast Cancer 2020; 28:448-458. [PMID: 33108608 DOI: 10.1007/s12282-020-01179-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/16/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Opioid binding protein/cell adhesion molecule-like (OPCML) has been demonstrated to be a tumor suppressor gene, as it has been shown in previous studies to play a tumor-suppressive role in a variety of cancers. However, the role of OPCML in breast tumorigenesis remains unclear. METHODS In this study, we analyzed OPCML expression in breast cancers and adjacent non-tumor tissue samples and examined its molecular function in the breast cancer-derived cell lines MDA-MB-231 and MCF7. RESULTS We found that OPCML was downregulated in most breast cancer samples but that this protein was expressed in most adjacent non-tumor samples. The loss or downregulation of OPCML is associated with hypermethylation of its promoter. Methylation of the OPCML promoter was detected in all breast cancer cell lines and primary tumors but was not detected in surgical margin tissues and normal breast tissues. Furthermore, functional assays showed that ectopic OPCML expression could inhibit breast tumor cell proliferation in vivo and in vitro and further suppresses tumor cell migration and invasion. CONCLUSION Our results show that OPCML exerts its tumor-suppressive functions in human breast cancer cells. Moreover, the promoter-specific hypermethylation of OPCML plays an important role in human breast cancer development.
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Affiliation(s)
- Bin Lian
- Department of Oncology Surgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Hong Li
- Department of Oncology Surgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yaobang Liu
- Department of Oncology Surgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Dahai Chai
- Department of Oncology Surgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yali Gao
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yangyang Zhang
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jia Zhou
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jinping Li
- Department of Oncology Surgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
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Vedeld HM, Folseraas T, Lind GE. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis - The promise of DNA methylation and molecular biomarkers. JHEP Rep 2020; 2:100143. [PMID: 32939446 PMCID: PMC7479288 DOI: 10.1016/j.jhepr.2020.100143] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/25/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly fatal malignancy of the bile ducts that arises in up to 20% of patients with primary sclerosing cholangitis (PSC). Current detection methods for CCA display suboptimal sensitivity and/or specificity, and there is no evidence-based screening strategy for CCA in patients with PSC. Consequently, CCA is often detected too late for surgical resection, contributing to the high mortality associated with this malignancy. Recently, biomarkers have emerged with potential to complement current detection methods, and/or be used for cancer surveillance in high-risk patient groups, including patients with PSC. Aberrant DNA methylation patterns represent promising biomarkers with great potential for CCA detection. Such aberrations are frequent in CCA, often occur early, and can be detected in liquid biopsies, including blood, bile and urine. This review summarises and highlights the most promising DNA methylation biomarkers identified for CCA detection so far, focusing on patients with PSC. Other promising molecular biomarkers for detection of PSC-associated CCA in liquid biopsies will also be briefly covered.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Guro Elisabeth Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
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Dong X, Zheng T, Zhang Z, Bai X, Li H, Zhang J. [Luteolin reverses OPCML methylation to inhibit proliferation of breast cancer MDA-MB-231 cells]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:550-555. [PMID: 32895125 DOI: 10.12122/j.issn.1673-4254.2020.04.16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To observe the effect of luteolin on the proliferation and expression of OPCML in breast cancer cell line MDA-MB-231. METHODS Cultured MDA-MB-231 cells were treated with luteolin at the concentrations of 5, 10 and 20 μmol/L for 24 or 48 h. MTT assay was used to detect cell proliferation and flow cytometry was used to detect the cell apoptosis. The expressions of OPCML mRNA and protein were detected using real-time quantitative PCR and Western blotting, respectively. OPCML gene methylation in the promoter region was detected using methylation-specific PCR (MSP), and the activity of methylase in the cells was analyzed. RESULTS MTT assay showed that treatment with luteolin at 5, 10 and 20 μmol/L for 24 h concentration-dependently decreased the viability of MDA-MB-231 cells (P < 0.05). Flow cytometry also showed that luteolin at different concentrations could induce apoptosis of MDA-MB-231 cells (P < 0.05). Luteolin dose-dependently induced the expression of OPCML mRNA and protein in MDA-MB-231 cells (P < 0.05), down-regulated the methylation status in the promoter region of OPCML gene, up-regulated the level of non-methylated OPCML, and reduced the activity of methylase in the cells (P < 0.05). CONCLUSIONS Luteolin inhibits the proliferation of MDA-MB-231 breast cancer cells probably by upregulating OPCML expression and its demethylation.
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Affiliation(s)
- Xinmin Dong
- Department of Oncology, Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, 010010, China
| | - Ti Zheng
- Medical Departmentn, Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, 010010, China
| | - Ziying Zhang
- Department of Basic Medicine, School of Pharmacology of Inner Mongolia Medical University, Hohhot 010110, China
| | - Xiling Bai
- Department of Interventional Riadiology, Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot 010010, China
| | - Hua Li
- Department of Oncology, Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, 010010, China
| | - Jian Zhang
- Department of Radiotherapy, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
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12
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Intuyod K, Armartmuntree N, Jusakul A, Sakonsinsiri C, Thanan R, Pinlaor S. Current omics-based biomarkers for cholangiocarcinoma. Expert Rev Mol Diagn 2019; 19:997-1005. [PMID: 31566016 DOI: 10.1080/14737159.2019.1673162] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a malignancy of the biliary tract. CCA generally has a low incidence worldwide but incidence is typically high in Southeast Asian countries, particularly in northeastern Thailand, where small liver-fluke (Opisthorchis viverrini) infection is endemic. CCA has a poor prognosis as most CCA patients present with advanced stages. Poor prognosis and worse outcomes are due to the lack of specific and early-stage CCA biomarkers. Areas covered: In this review, we discuss the use of CCA tissues, serum and bile samples as sources of diagnostic and prognostic markers by using -omics approaches, including genomics, epigenomics, transcriptomics and proteomics. The current state of the discovery of molecular candidates and their potential to be used as diagnostic and prognostic biomarkers for CCA are summarized and discussed. Expert opinion: Various potential molecules have been discovered, some of which have been verified as diagnostic biomarkers for CCA. However, most identified molecules require much further evaluation to help us find markers with high specificity, low cost and ease-of-use in routine diagnostic laboratories.
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Affiliation(s)
- Kitti Intuyod
- Department of Parasitology, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Napat Armartmuntree
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Faculty of Associated Medical Sciences, Khon Kaen University , Khon Kaen , Thailand
| | - Chadamas Sakonsinsiri
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Raynoo Thanan
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand.,Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University , Khon Kaen , Thailand
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13
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Birtley JR, Alomary M, Zanini E, Antony J, Maben Z, Weaver GC, Von Arx C, Mura M, Marinho AT, Lu H, Morecroft EVN, Karali E, Chayen NE, Tate EW, Jurewicz M, Stern LJ, Recchi C, Gabra H. Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions. Nat Commun 2019; 10:3134. [PMID: 31316070 PMCID: PMC6637204 DOI: 10.1038/s41467-019-10966-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 06/06/2019] [Indexed: 11/28/2022] Open
Abstract
OPCML, a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases of tumor sequences, the observation of OPCML somatic missense mutations from various tumor types and the impact of these mutations on OPCML function, by solving the X-ray crystal structure of this glycoprotein to 2.65 Å resolution. OPCML consists of an extended arrangement of three immunoglobulin-like domains and homodimerizes via a network of contacts between membrane-distal domains. We report the generation of a panel of OPCML variants with representative clinical mutations and demonstrate clear phenotypic effects in vitro and in vivo including changes to anchorage-independent growth, interaction with activated cognate receptor tyrosine kinases, cellular migration, invasion in vitro and tumor growth in vivo. Our results suggest that clinically occurring somatic missense mutations in OPCML have the potential to contribute to tumorigenesis in a variety of cancers.
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Affiliation(s)
- James R Birtley
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
- UCB Pharma, Bath Road, Slough, SL1 3WE, UK
| | - Mohammad Alomary
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Elisa Zanini
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Jane Antony
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Zachary Maben
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
| | - Grant C Weaver
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
| | - Claudia Von Arx
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Manuela Mura
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Aline T Marinho
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Haonan Lu
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Eloise V N Morecroft
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
- Department of Chemistry, Imperial College London, Wood Lane, London, W12 0BZ, UK
| | - Evdoxia Karali
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Naomi E Chayen
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK
| | - Edward W Tate
- Department of Chemistry, Imperial College London, Wood Lane, London, W12 0BZ, UK
| | - Mollie Jurewicz
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01655, USA
| | - Lawrence J Stern
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
| | - Chiara Recchi
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK.
| | - Hani Gabra
- Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK.
- Clinical Discovery Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, SG8 6HB, UK.
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14
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Wasenang W, Chaiyarit P, Proungvitaya S, Limpaiboon T. Serum cell-free DNA methylation of OPCML and HOXD9 as a biomarker that may aid in differential diagnosis between cholangiocarcinoma and other biliary diseases. Clin Epigenetics 2019; 11:39. [PMID: 30832707 PMCID: PMC6399934 DOI: 10.1186/s13148-019-0634-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 02/18/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct epithelial cell lining. The misdiagnosis of CCA and other biliary diseases may occur due to the similarity of clinical manifestations and blood tests resulting in inappropriate or delayed treatment. Thus, an accurate and less-invasive method for differentiating CCA from other biliary diseases is inevitable. METHODS We quantified methylation of OPCML, HOXA9, and HOXD9 in serum cell-free DNA (cfDNA) of CCA patients and other biliary diseases using methylation-sensitive high-resolution melting (MS-HRM). Their potency as differential biomarkers between CCA and other biliary diseases was also evaluated by using receiver operating characteristic (ROC) curves. RESULTS The significant difference of methylation levels of OPCML and HOXD9 was observed in serum cfDNA of CCA compared to other biliary diseases. Assessment of serum cfDNA methylation of OPCML and HOXD9 as differential biomarkers of CCA and other biliary diseases showed the area under curve (AUC) of 0.850 (0.759-0.941) for OPCML which sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 80.00%, 90.00%, 88.88%, 81.81%, and 85.00%, respectively. The AUC of HOXD9 was 0.789 (0.686-0.892) with sensitivity, specificity, PPV, NPV, and accuracy of 67.50%, 90.00%, 87.09%, 73.46%, and 78.75%, respectively. The combined marker between OPCML and HOXD9 showed sensitivity, specificity, PPV, and NPV of 62.50%, 100%, 100%, and 72.72%, respectively, which may be helpful to prevent a misdiagnosis between CCA and other biliary diseases. CONCLUSIONS Our findings suggest the application of serum cfDNA methylation of OPCML and HOXD9 for differential diagnosis of CCA and other biliary diseases due to its less invasiveness and clinically practical method which may benefit the patients by preventing the misdiagnosis of CCA and avoiding unnecessary surgical intervention.
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Affiliation(s)
- Wiphawan Wasenang
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
- Biomedical Sciences, Graduate School, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Ponlatham Chaiyarit
- Research Group of Chronic Inflammatory Oral Diseases and Systemic Diseases Associated with Oral Health, Department of Oral Diagnosis, Faculty of Dentistry, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Siriporn Proungvitaya
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Temduang Limpaiboon
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
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15
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Yamashita K, Hosoda K, Nishizawa N, Katoh H, Watanabe M. Epigenetic biomarkers of promoter DNA methylation in the new era of cancer treatment. Cancer Sci 2018; 109:3695-3706. [PMID: 30264476 PMCID: PMC6272087 DOI: 10.1111/cas.13812] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 09/20/2018] [Accepted: 09/22/2018] [Indexed: 12/21/2022] Open
Abstract
Promoter DNA methylation, which occurs on cytosine nucleotides across CpG islands, results in gene silencing and represents a major epigenetic alteration in human cancer. Methylation-specific PCR can amplify these modifications as markers in cancer cells. In the present work, we rigorously review the published literatures describing DNA methylation in the promoters of critical tumor suppressor genes; detection of promoter DNA methylation in various body fluids permits early detection of cancer cells during perioperative courses of clinical treatment. The latest whole-genome comprehensive explorations identified excellent epigenetic biomarkers that could be detected at high frequency with high specificity; these biomarkers, which are designated highly relevant methylation genes (HRMG), permit the discrimination of tumor tissues from the corresponding normal tissues; these markers are also associated with unique cancer phenotypes, including dismal prognosis. In humans, HRMG include the CDO1, GSHR, RASSF1 and SFRP1 genes, with these markers permitting discrimination depending on the organs tested. The combination of several HRMG increased the early detection of cancer and exhibited reliable surveillance potential in human body fluids. Cancer clinics using such epigenetic biomarkers are entering a new era of enhanced decision-making with the potential for improved cancer prognosis.
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Affiliation(s)
- Keishi Yamashita
- SurgeryKitasato University School of MedicineSagamiharaKanagawaJapan
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical FrontiersKitasato University School of MedicineSagamiharaKanagawaJapan
| | - Kei Hosoda
- SurgeryKitasato University School of MedicineSagamiharaKanagawaJapan
| | | | - Hiroshi Katoh
- SurgeryKitasato University School of MedicineSagamiharaKanagawaJapan
| | - Masahiko Watanabe
- SurgeryKitasato University School of MedicineSagamiharaKanagawaJapan
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16
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A DNA-Methylated Sight on Autoimmune Inflammation Network across RA, pSS, and SLE. J Immunol Res 2018; 2018:4390789. [PMID: 30159339 PMCID: PMC6109517 DOI: 10.1155/2018/4390789] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 07/08/2018] [Indexed: 12/14/2022] Open
Abstract
Methylation variabilities of inflammatory cytokines play important roles in the development of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS). With heightened focus on personalized and precise medicine, it is necessary to compare and contrast the difference and similarity of cytokine methylation status between the 3 most classic autoimmune diseases (AIDs). In this study, we integrated 5 Cytokine-Chips from genome-wide DNA methylation datasets of the 3 kind of AIDs, delta-beta value was calculated for intergroup difference, and comprehensive bioinformatics analyses of cytokine genes with aberrant methylations were performed. 125 shared differential methylation variabilities (DMVs) were identified. There were 102 shared DMVs with similar methylation status; 3 hypomethylated differential methylation regions (DMRs) across the AIDs were found, and all 3 DMRs were hypomethylated. DMRs (AZU1, LTBR, and RTEL1) were likely to serve as activator in the inflammatory process. Particularly, AZU1 and LTBR with hypomethylated TSS and first exon located in the promoter regions were able to trigger inflammation signaling cascades and play critical roles in autoimmune tautology. Moreover, functional epigenetic module (FEM) algorithm showed that different inflammatory networks are involved in different AIDs; 5 hotspots were identified as biologically plausible pathways in inducing or perpetuating of inflammation which are epigenetically deregulated in AIDs. We concluded methylation variabilities among the same cytokines can greatly impact the perpetuation of inflammatory process or signal pathway of AIDs. Differentiating the cytokine methylation status will serve as valuable resource for researchers alike to gain better understanding of the epigenetic mechanisms of the three AIDs. Even more importantly, better understanding of cytokine methylation variability existing between the three classic AIDs will aid in identification of potential epigenetic biomarkers and therapeutic targets. This trial is registered with ChiCTR-INR-16010290, a clinical trial for the treatment of rheumatoid arthritis with Warming yang and Smoothening Meridians.
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17
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Zhang N, Xu J, Wang Y, Heng X, Yang L, Xing X. Loss of opioid binding protein/cell adhesion molecule-like gene expression in gastric cancer. Oncol Lett 2018; 15:9973-9977. [PMID: 29805691 DOI: 10.3892/ol.2018.8562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Accepted: 05/17/2017] [Indexed: 12/11/2022] Open
Abstract
Previous studies have reported that the expression of the opioid binding protein/cell adhesion molecule-like (OPCML) gene was frequently downregulated in various of types of cancer. However, little is known regarding the expression of the OPCML gene in gastric cancer. The present study identified that OPCML was downregulated in the gastric cancer SGC7901, KATO III, MKN45, MKN74, SNU1, AGS, N87 and a gastric mucosa cell line GES1, compared with normal gastric tissues by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To investigate whether the downregulation of OPCML was due to promoter hypermethylation, the methylation of the OPCML promoter was assessed by methylation-specific polymerase chain reaction. Hypermethylation of the OPCML promoter was observed in the gastric cancer MKN45 cell lines, but was not as evident in normal gastric tissue. The methylation inhibitor 5-aza-2'-deoxycytidine was used to remove the methylation of the OPCML gene promoter, following which the expression of OPCML was restored. In addition, the function of the OPCML gene was studied in vitro, and it was found that the restoration expression of OPCML could lead to the suppression of cell growth. In conclusion, the present study has shown that OPCML, which acts as a tumor suppressor, was silenced in gastric cancer cell lines via aberrant hypermethylation of the promoter CpG islands, which may provide a novel molecular approach for the early diagnosis of gastric cancer.
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Affiliation(s)
- Ning Zhang
- Department of Respiratory Disease, Affiliated LuoHu Hospital of Shenzhen University, Shenzhen, Guangdong 518001, P.R. China
| | - Jide Xu
- Department of Physiology, Guangzhou Medical University, Guangzhou, Guangdong 510000, P.R. China
| | - Yuhong Wang
- Department of Endoscopy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510000, P.R. China
| | - Xuhua Heng
- Department of Cardiogy, Affiliated Hospital of Panzhihua University, Panzhihua, Sichuan 617000, P.R. China
| | - Liteng Yang
- Department of Respiratory Disease, Affiliated LuoHu Hospital of Shenzhen University, Shenzhen, Guangdong 518001, P.R. China
| | - Xiangbin Xing
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510000, P.R. China
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18
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Liu S, Chen X, Chen R, Wang J, Zhu G, Jiang J, Wang H, Duan S, Huang J. Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer. Oncotarget 2018; 8:36354-36367. [PMID: 28422739 PMCID: PMC5482660 DOI: 10.18632/oncotarget.16754] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 03/21/2017] [Indexed: 12/14/2022] Open
Abstract
Wnt signal pathway genes are known to be involved with cancer development. Here we tested the hypothesis whether DNA methylation of genes part of the Wnt signaling pathway could help the diagnosis of non-small cell lung cancer (NSCLC). The methylation levels of SFRP1, SFRP2, WIF1 and PRKCB in 111 NSCLC patients were evaluated by quantitative methylation-specific PCR (qMSP). Promoter methylation levels of four candidate genes were significantly higher in tumor tissues compared with the adjacent tissues. SFRP1, SFRP2 and PRKCB genes were all shown to be good predictors of NSCLC risk (SFRP1: AUC = 0.711; SFRP2: AUC = 0.631; PRKCB: AUC = 0.650). The combined analysis showed that the methylation status of the four genes had a sensitivity of 70.3% and a specificity of 73.9% in the prediction of NSCLC risk for study cohort. A higher diagnostic value with an AUC of 0.945 (95% CI: 0.923–0.967, sensitivity: 90.6%, specificity: 93.0%) was found in TCGA cohort. In addition, SFRP1 and SFRP2 hypermethylation events were specific to male patients. Further TCGA data mining analysis suggested that SFRP1_cg15839448, SFRP2_cg05774801, and WIF1_cg21383810 were inversely associated with the host gene expression. Moreover, GEO database analysis showed that 5′-Aza-deoxycytidine was able to upregulate gene expression in several lung cancer cell lines. Subsequent dual-luciferase reporter assay showed a crucial regulatory function of PRKCB promoter. In summary, our study showed that a panel of Wnt signal pathway genes (SFRP1, SFRP2, WIF1 and PRKCB) had the potential as methylation biomarkers in the diagnosis of NSCLC.
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Affiliation(s)
- Shunlin Liu
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Xiaoying Chen
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ruhua Chen
- Department of Respiratory Medicine, Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, China
| | - Jinzhi Wang
- Department of Cell Biology, School of Medicine, Soochow University, Suzhou, Jiangsu 215007, China
| | - Guoliang Zhu
- Department of Pathology, Huzhou First People's Hospital, Huzhou, Zhejiang 313000, China
| | - Jianzhong Jiang
- Department of Geriatrics, Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu 214200, China
| | - Hongwei Wang
- Realgen Biotechnology Co., Ltd. Zhangjiang High Technology Park, Shanghai 201203, China
| | - Shiwei Duan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Jianan Huang
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
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19
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Vincent KM, Postovit LM. Matricellular proteins in cancer: a focus on secreted Frizzled-related proteins. J Cell Commun Signal 2018; 12:103-112. [PMID: 28589318 PMCID: PMC5842174 DOI: 10.1007/s12079-017-0398-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 06/02/2017] [Indexed: 12/31/2022] Open
Abstract
Tumours are complex entities, wherein cancer cells interact with myriad soluble, insoluble and cell associated factors. These microenvironmental mediators regulate tumour growth, progression and metastasis, and are produced by cancer cells and by stromal components such as fibroblast, adipocytes and immune cells. Through their ability to bind to extracellular matrix proteins, cell surface receptors and growth factors, matricellular proteins enable a dynamic reciprocity between cancer cells and their microenvironment. Hence, matricellular proteins play a critical role in tumour progression by regulating where and when cancer cells are exposed to key growth factors and regulatory proteins. Recent studies suggest that, in addition to altering Wingless (Wnt) signalling, certain members of the Secreted Frizzled Related Protein (sFRP) family are matricellular in nature. In this review, we outline the importance of matricellular proteins in cancer, and discuss how sFRPs may function to both inhibit and promote cancer progression in a context-dependent manner. By considering the matricellular functionality of sFRPs, we may better understand their apparently paradoxical roles in cancers.
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Affiliation(s)
- Krista Marie Vincent
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 114th St and 87th Ave, Edmonton, AB T6G 2E1 Canada
- Department of Anatomy and Cell Biology, Faculty of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St, London, ON N6A 3K7 Canada
| | - Lynne-Marie Postovit
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 114th St and 87th Ave, Edmonton, AB T6G 2E1 Canada
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20
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Mo S, Su Z, Heng B, Chen W, Shi L, Du X, Lai C. SFRP1 Promoter Methylation and Renal Carcinoma Risk: A Systematic Review and Meta-Analysis. J NIPPON MED SCH 2018; 85:78-86. [PMID: 29731501 DOI: 10.1272/jnms.2018_85-13] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIM Epigenetic inactivation of tumor suppressor genes is an important molecular mechanism in the formation and development of human tumors. The purpose of our study was to evaluate the correlation between the methylation level of the secreted frizzled-related protein 1 (SFRP1) gene and the risk of renal cell carcinoma (RCC). METHODS The relevant literature was searched in detail in several electronic databases. The methodological heterogeneity was analyzed by meta-regression and subgroup analyses. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated to summarize the dichotomous outcomes of our meta-analysis. RESULTS The ten included articles contained 535 RCC samples and 475 normal controls. The results demonstrated that the methylation level of the SFRP1 promoter region was significantly correlated with an increased incidence of RCC (OR=13.72; 95% CI: 6.01-31.28; P=0.000). Furthermore, the eligible studies that had sufficient clinical data about the RCC cases were included in the analysis, and the results indicated that the frequency of SFRP1 promoter methylation was associated with a higher histological grade (P=0.000), tumor stage (P=0.033), tumor size (≥5 cm; P=0.029), and distant metastasis (P=0.047). CONCLUSION Our results indicate that the methylation level of the SFRP1 promoter region is increased in patients with RCC compared to normal controls and might be involved in the occurrence and development of RCC. Additional well-designed studies are needed to further verify our conclusions.
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Affiliation(s)
- Shijie Mo
- Department of Urology, The First Affiliated Hospital, Jinan University
| | - Zexuan Su
- Department of Urology, The First Affiliated Hospital, Jinan University
| | - Baoli Heng
- Department of Urology, The First Affiliated Hospital, Jinan University
| | - Weijun Chen
- Department of Urology, The First Affiliated Hospital, Jinan University
| | - Liping Shi
- Department of Urology, The First Affiliated Hospital, Jinan University
| | - Xinghua Du
- Department of Urology, The First Affiliated Hospital, Jinan University
| | - Caiyong Lai
- Department of Urology, The First Affiliated Hospital, Jinan University
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21
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Bhat S, Kabekkodu SP, Varghese VK, Chakrabarty S, Mallya SP, Rotti H, Pandey D, Kushtagi P, Satyamoorthy K. Aberrant gene-specific DNA methylation signature analysis in cervical cancer. Tumour Biol 2017; 39:1010428317694573. [PMID: 28351298 DOI: 10.1177/1010428317694573] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024] Open
Abstract
Multicomponent molecular modifications such as DNA methylation may offer sensitive and specific cervical intraepithelial neoplasia and cervical cancer biomarkers. In this study, we tested cervical tissues at various stages of tumor progression for 5-methylcytosine and 5-hydroxymethylcytosine levels and also DNA promoter methylation profile of a panel of genes for its diagnostic potential. In total, 5-methylcytosine, 5-hydroxymethylcytosine, and promoter methylation of 33 genes were evaluated by reversed-phase high-performance liquid chromatography, enzyme-linked immunosorbent assay based technique, and bisulfate-based next generation sequencing. The 5-methylcytosine and 5-hydroxymethylcytosine contents were significantly reduced in squamous cell carcinoma and receiver operating characteristic curve analysis showed a significant difference in (1) 5-methylcytosine between normal and squamous cell carcinoma tissues (area under the curve = 0.946) and (2) 5-hydroxymethylcytosine levels among normal, squamous intraepithelial lesions and squamous cell carcinoma. Analyses of our next generation sequencing results and data from five independent published studies consisting of 191 normal, 10 low-grade squamous intraepithelial lesions, 21 high-grade squamous intraepithelial lesions, and 335 malignant tissues identified a panel of nine genes ( ARHGAP6, DAPK1, HAND2, NKX2-2, NNAT, PCDH10, PROX1, PITX2, and RAB6C) which could effectively discriminate among the various groups with sensitivity and specificity of 80%-100% (p < 0.05). Furthermore, 12 gene promoters (ARHGAP6, HAND2, LHX9, HEY2, NKX2-2, PCDH10, PITX2, PROX1, TBX3, IKBKG, RAB6C, and DAPK1) were also methylated in one or more of the cervical cancer cell lines tested. The global and gene-specific methylation of the panel of genes identified in our study may serve as useful biomarkers for the early detection and clinical management of cervical cancer.
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Affiliation(s)
- Samatha Bhat
- 1 Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, India
| | - Shama Prasada Kabekkodu
- 1 Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, India
| | - Vinay Koshy Varghese
- 1 Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, India
| | - Sanjiban Chakrabarty
- 1 Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, India
| | - Sandeep P Mallya
- 1 Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, India
| | - Harish Rotti
- 1 Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, India
| | - Deeksha Pandey
- 2 Department of Obstetrics & Gynaecology, Kasturba Medical College, Manipal University, Manipal, India
| | - Pralhad Kushtagi
- 3 Department of Obstetrics & Gynaecology, Kasturba Medical College, Manipal University, Mangalore, India
| | - Kapaettu Satyamoorthy
- 1 Department of Cell and Molecular Biology, School of Life Sciences, Manipal University, Manipal, India
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Branchi V, Schaefer P, Semaan A, Kania A, Lingohr P, Kalff JC, Schäfer N, Kristiansen G, Dietrich D, Matthaei H. Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract. Clin Epigenetics 2016; 8:133. [PMID: 27999621 PMCID: PMC5153824 DOI: 10.1186/s13148-016-0299-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 11/29/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Biliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC. METHODS Relative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival. RESULTS SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865-0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631-0.873). CONCLUSIONS SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.
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Affiliation(s)
- V Branchi
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - P Schaefer
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - A Semaan
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - A Kania
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - P Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - J C Kalff
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - N Schäfer
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - G Kristiansen
- Institute of Pathology, University Hospital Bonn, Bonn, Germany
| | - D Dietrich
- Institute of Pathology, University Hospital Bonn, Bonn, Germany.,Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany
| | - H Matthaei
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
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The key culprit in the pathogenesis of systemic lupus erythematosus: Aberrant DNA methylation. Autoimmun Rev 2016; 15:684-9. [DOI: 10.1016/j.autrev.2016.03.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 02/28/2016] [Indexed: 01/21/2023]
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Viterbo D, Gausman V, Gonda T. Diagnostic and therapeutic biomarkers in pancreaticobiliary malignancy. World J Gastrointest Endosc 2016; 8:128-142. [PMID: 26862363 PMCID: PMC4734972 DOI: 10.4253/wjge.v8.i3.128] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/17/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are two malignancies that carry significant morbidity and mortality. The poor prognoses of these cancers are strongly related to lack of effective screening modalities as well as few therapeutic options. In this review, we highlight novel biomarkers that have the potential to be used as diagnostic, prognostic and predictive markers. The focus of this review is biomarkers that can be evaluated on endoscopically-obtained biopsies or brush specimens in the pre-operative setting. We also provide an overview of novel serum based markers in the early diagnosis of both PDAC and CCA. In pancreatic cancer, the emphasis is placed on prognostic and theranostic markers, whereas in CCA the utility of molecular markers in diagnosis and prognosis are highlighted.
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